(1) Field of the Invention
The present invention generally relates to a method for preventing or reducing a photosensitivity and/or phototoxicity reaction which may be caused by a once-per-day dose of an over-the-counter or prescription medication which causes a photosensitivity and/or phototoxicity reaction in a human or animal patient comprising administering the prescribed or suggested dose of the medication to the patient during the evening or early morning hours, between the hours of about 4:00 p.m. and about 4:00 a.m.
The present invention also generally relates to a method for administering a once-per-day dose of an over-the-counter or prescription medication which causes a photosensitivity and/or phototoxicity reaction to a human or animal patient in a manner which prevents or reduces such a reaction comprising administering the prescribed or suggested dose of the medication to the patient during the evening or early morning hours, between the hours of about 4:00 p.m. and about 4:00 a.m.
The present invention also generally relates to, in a method for administering a therapeutically effective amount of a once-a-day medication which medication in such a once-a-day therapeutic amount achieves a concentration in the blood which causes a photosensitivity and/or phototoxicity reaction in the patient to whom the medication is administered, an improvement in the method comprising administering the medication to the patient at a time sufficient for the blood level of such medication to be at a concentration which is less than a concentration which produces a photosensitivity and/or phototoxicity reaction during the daylight hours.
The present invention also generally relates to a method for treating an infection in a patient in a manner which prevents or reduces a photosensitivity and/or phototoxicity reaction which method comprises orally administering to the patient a once-a-day dose of about 25 mg to about 700 mg of lomefloxacin hydrochloride between the hours of about 4:00 p.m. and about 4:00 a.m.
The present invention also generally relates to an article of manufacture comprising: (1) a packaging material, and (2) a once-a-day dose of an over-the-counter or prescription medication which causes a photosensitivity and/or a phototoxicity reaction in a human or animal patient contained within said packaging material, wherein such a reaction is prevented or reduced by administering the medication to the patient during the evening or early morning hours, between the hours of about 4:00 p.m. and about 4:00 a.m., and wherein the packaging material comprises a label which indicates that such a reaction is prevented or reduced by administering the medication to the patient during the evening or early morning hours, between the hours of about 4:00 p.m. and about 4:00 a.m., and/or that such medication is to be administered between the hours of about 4:00 p.m. and about 4:00 a.m., and/or wherein the packaging material is arranged in a manner which releases the medication to the patient during the evening or early morning hours, between the hours of about 4:00 p.m. and about 4:00 a.m.
Deleterious reactions caused by sun exposure can be broadly classified into sunburns or chemically-induced photosensitivity reactions. The reactions produced by such interaction leads to erythema, fever and, at times, blisters similar to those produced by moderate to severe sunburn. Photoreactions may occur through light clothing, such as T-shirts or blouses.
The solar spectra that commonly affect human skin are UVB (ultraviolet B, 290 to 320 nm) and UVA (ultraviolet A, 320 to 400 nm). UVB is known as the "sunburn spectrum," which can cause burning, tanning, aging and carcinogenic changes in the skin. UVA is erythrogenic, but the amount of energy required to induce an erythemic effect is 1000 times greater than for UVB. It has been shown for most drugs associated with photosensitivity reactions that wavelengths from approximately 320 nm to approximately 400 nm (UVA) are most important for photoreactions. These reactions are evoked when UVA light energy is absorbed by an appropriate concentration of drug in the skin. The resulting photochemical reactions can damage cell membranes and lysosomes, and induce an exaggerated sunburn with intense redness, edema and occasionally blisters.
Sunburn is the result of the penetration of the skin by ultraviolet (UV) light, primarily the UVB light. An estimated 95% of UVB radiation reaching skin is absorbed.
The prolonged exposure to UVA light can produce mild burn and hyperpigmentation. UVA radiation penetrates well through the epidermis, but tends to tan more than burn the skin. However, UVA radiation which, while usually burning less, will provide a severe burn when an exposed individual has taken a sensitizing agent, such as a medication which causes a photosensitivity and/or phototoxicity reaction. UVA radiation is not limited to direct sun exposure. Cloud cover, shady areas, light through glass windows and/or car windows may still cause a photosensitivity reaction.
UVA radiation, which is commonly associated with drug-induced phototoxic or photoallergic reactions, has a relatively constant level during daylight hours. UVB radiation, on the other hand, which causes common sunburn, and is a dose-related risk for melanoma, has its strongest effect between 10:00 a.m. and 2:00 p.m. Thus, avoiding the sun between these hours may help to minimize ordinary sunburn, but may not have the same effect on drug-induced photoreactions.
Sunburn is a complex inflammatory process causing dyskeratotic cells, spongiosis, vacuolation of keratinocytes and edema from capillary leakage 12 to 24 hours after exposure to light (from the sun, or from artificial sources). Erythema is the most common symptom. Erythema is a prostaglandin-mediated vasodilary effect, an attempt to protect the epidermis and minimize further damage. At the cellular level of the skin, sun radiation has been shown to reduce the phospholipid content of the skin and alter its cholesterol, a substance which is a contributor to the stability of cell membranes. Sun radiation has also been shown to act on intracellular cell bodies known as lysosomes, which play an important role in controlling the conversion of the living cells of epidermis to horny (keratinized) material which is found as the protective outer layer of the skin. Destruction of lysosomes is believed to be responsible for prematurely keratinized cells. Substances discharged from damaged lysosomes may be responsible for characteristic symptoms of severe sunburn, such as dilation of the blood vessels and fever.
It is well known that numerous, different over-the-counter and prescription medications, including the quinolone class of antibiotics, in widespread use throughout the world today, can cause undesirable and, often, severe and painful photosensitivity and/or phototoxicity reactions in patients exposed to direct or indirect sunlight, or to artificial ultraviolet light. Many of the patients which have experienced such reactions have had to be hospitalized for several days as a result of such reactions, and have required i.v. therapy and other medications. Consequently, these medications, including all quinolone antibiotics, contain appropriate warnings concerning photosensitivity and/or phototoxicity reactions in their product labeling. Patients are advised to avoid excessive sunlight and artificial ultraviolet light while receiving these drugs, and to discontinue therapy if phototoxicity occurs.
In order for medications to cause photosensitivity and/or phototoxicity reactions, the skin has to be exposed to a specified radiation wave length band. The resulting reactions include acute, abnormal sunburn responses (blistered and/or peeling skin, edema, swelling of the face and/or limbs, rashes, first, second and/or third degree burns, itching, pain to the skin, eyes and/or joints, nausea, vomiting, diarrhea, fever, chills, confusion, protein in the urine, red, swollen, tearing and/or photophobic eyes, ulcers, etc.). A summary of commonly-used, commercially-available medications, the type of photoreaction caused thereby, as well as their action spectrum, is presented in Table 1 below.
TABLE 1 ______________________________________ SYSTEMIC PHOTOSENSITIZERS Type of Action Name Photoreaction Spectrum (nm) ______________________________________ Sulfonamides Phototoxic and photoallergic 290-320 Sulfonylureas 290-360 (tolbutamide, chlorpropamide) Chlorothiazides Phototoxic and photoallergic 290-320 320-400 Phenothiazines Phototoxic, urticaria eruption, 290-400 gray-blue hyperpigmentation Antibiotics Phototoxic and photoallergic 320-400 (tetracyclines, bullae griseofulvin, nalidixic acid) Furocoumarins Phototoxic (psoralens) Nonsteroidal anti- Phototoxic and photoallergic Unknown inflammatory agents Anticancer drugs Phototoxic Unknown (DTIC, fluorouracil, methotrexate, vinblastine) Estrogens, Phototoxic, melasma 290-320 progestins, and other drugs Chlordiazepoxide Photoallergic 290-360 (Librium) Cyclamates Phototoxic and photoallergic 290-360 Quinidine, Photoallergic 320-400 quinine ______________________________________
Quinolone antibiotics are known to produce photoreactions, which are primarily phototoxic in nature, in humans and in animals.
MAXAQUIN.RTM. (lomefloxacin hydrochloride), which is available from G. D. Searle & Co. (Skokie, Ill.), as well as all marketed quinolones, exhibits a dose-dependent, drug-induced, UVA required photosensitivity reaction. The most clinically-relevant human serum levels for lomefloxacin HCl are approximately 0.2 to approximately 5 micrograms per ml of plasma.
Until recently, the mechanism of photoreactions of quinolones were considered unknown. A number of in vitro studies have now been reported on the mechanism of quinolones, including lomefloxacin hydrochloride. Reaction of quinolones in the skin with UVA light may generate singlet oxygen, free radicals or other toxic by-products. These substances, in turn, bind to cellular DNA leading to lipid peroxidation, a critical event in photo-induced cellular lysis.
There clearly exists a need for a method for preventing or reducing a photosensitivity and/or phototoxicity reaction which may be caused by an over-the-counter or prescription medication which causes a photosensitivity and/or phototoxicity reaction in a patient.
Until the discovery of the present invention, in order to reduce the incidence rate and severity of photosensitivity and/or phototoxicity reactions, such as to over-the-counter and prescription medications which cause photosensitivity and/or phototoxicity reactions, for example lomefloxacin hydrochloride, patients for which these medications were prescribed had to minimize their exposure to UVA radiation by wearing appropriate clothing, and by applying suntan creams with high SPF and effective blockage of UVA radiation. In addition, patients had to be careful to minimize their exposure to direct or indirect sunlight during, and for a few days after, receiving medications such as MAXAQUIN.RTM..
It has now been discovered that a method for preventing or reducing photosensitivity and/or phototoxicity reactions in patients for which over-the-counter and/or prescription medications which cause photosensitivity and/or phototoxicity reactions, such as MAXAQUIN.RTM., have been prescribed is through the reduction of the concentration of the medication in the blood and, consequently, in the skin, during the high UVA and/or UVB radiation periods. This can be achieved by administering a single daily dose of the medication to the patients during the evening, or during the early morning hours, preferably before 4:00 a.m., and more preferably just before dinner.
(2) Description of the Related Art
U.S. Pat. No. 4,528,287, which is incorporated herein by reference, discloses piperazinyl-quinoline-3-carboxylic acids, pharmaceutically-acceptable salts thereof, a process for preparing them, and a pharmaceutical composition which contains these compounds as an active ingredient.
The concept of administering medications in a manner which minimizes skin levels of drug during periods of peak daily sunlight is novel, and is not known to be discussed in the literature.
There are generally no specific instructions given to a patient concerning the time of day during which a patient should take his once-a-day medication. Generally, once-a-day medications are described and/or prescribed and/or recommended for use in terms of a "daily," rather than an "evening," dose. See, for example, the dosage information for MAXAQUIN.RTM. which is present in the Physician's Desk Reference (47th Edition, Medical Economics Data, Montrale, N.J., 1993), which is described in terms of a "daily" dose. By convention, most once-a-day medications are taken in the late morning hours (between the hours of 6:00 a.m. and 11:00 a.m.), generally before, with, or just after, breakfast.